Many skin or mucosal membrane conditions or disorders result from inflammation caused by, inter alia bacteria, fungi, viruses, parasites, autoimmune disorders, allergens, environmental conditions, such as extreme temperatures, wounds, hormones and/or malignant agents. Thus, inflammation can be associated with numerous underlying conditions ranging from dry skin to infections to cancer, as well as being symptomatic of inflammatory disorders such as dermatitis.
Inflammation is often characterized by a strong infiltration of leukocytes at the site of inflammation, particularly neutrophils (polymorphonuclear cells). These cells promote tissue damage by releasing toxic substances at the vascular wall or in uninjured tissue.
Neutrophil infiltration results from amplifying cascades of cell-cell communication involving signal transduction proteins such as G-proteins that can facilitate intracellular regulation and intercellular communication by interacting with a wide range of different regulatory receptor-transducer proteins such as membrane-bound receptors. For these interactions to occur, many of the signal transduction proteins, including virtually all G-proteins, must first be modified by the post-translational addition of a C15 farnesyl or C20 geranylgeranyl polyisoprenoid moiety in thioether linkage to a cysteine residue located at or near the carboxy terminus within a so-called CAAX box or related cysteine-containing sequence. Carboxy terminal polyisoprenoid cysteines that ultimately result from these modifications are subject to methylesterification by a specific membrane-associated S-adenosylmethionine-dependent polyisoprenyl-S-cysteinyl methyltransferase. Compounds that can inhibit these enzymatic reactions or otherwise alter the interactions among polyisoprenylated signal transduction proteins, such as G-proteins and the protein regulatory targets with which they interact, or other intracellular signaling proteins, can be used to mitigate leukocyte responses and, theoretically, to treat inflammatory-related conditions. (see e.g. Volker et al., Methods Enzymol., 1995, 250, 216-225)
One such compound is N-acetylfarnesyl-cysteine (AFC). AFC has been shown to inhibit membrane-associated polyisoprenoid methyl transferase and to block some neutrophil, macrophage, and platelet responses in vitro. Unfortunately, AFC requires high concentrations for efficacy and is expected to result in generalized systemic effects and multiple side effects since it interferes with a central cell regulation mechanism, characteristics which would seem to preclude its use in vivo. However, because such inhibitory compounds have the potential to be highly efficacious, there is a need in the art for compositions containing these compounds that can act as a safe and effective antidote for skin and mucosal membrane conditions.